This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We are using a rhesus macaque model of HIV infection and AIDS to develop potential vaccine strategies against the clade C strain of HIV (HIV-C), the world's most prevalent strain. For efficacy testing of potential vaccines against HIV-C, we developed hybrid viruses, called SHIVs, by combining genetic components of a monkey AIDS virus with a portion of HIV called Envelope (Env);we developed two such viruses using Envs from two HIV-C strains isolated from African infants. Our approach to vaccine development is to generate: 1) immune cell-based responses to multiple viral components, and 2) neutralizing antibody-based immunity to Env. The Env of each HIV strain is unique and mimic reality where vaccinated individuals will not be exposed to HIV strains identical to that used for vaccine preparation. We deliberately challenged our vaccinated monkeys with SHIVs that are Env-mismatched compared to the Env used for vaccination. In one study, monkeys immunized as infants against multiple structural components of SHIV showed protection against both low-dose and high-dose challenges with two forms of a clade C SHIV, including one case of complete protection. In a more recent study, similarly vaccinated macaques showed delays until the onset of viremia and peak viremia, and lower plasma viral loads compared with controls;one third of these vaccines had no evidence of viremia. We are also following a set of animals, previously vaccinated and/or exposed to clade C SHIVs that have maintained high levels of broadly-reactive neutralizing antibodies (nAbs). We are analyzing the fine-specificity of the antibody responses in these animals to identify specific sites of envelope recognized by nAbs that are common among different HIV strains. This information will be important for the design of vaccine components to raise antibodies that would neutralize a broad range of HIV strains in vaccinated humans.